A number of benzimidazole derivatives are known in the prior art. Thus, for example, International Patent Application WO 00/01704 discloses benzimidazole derivatives which have valuable pharmacological properties, particularly an antithrombotic activity, which is based, for example, on a thrombin-inhibiting or factor Xa-inhibiting activity.
By virtue of their pharmacological properties, the compounds (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and the monohydrochloride thereof may be used for the prevention and treatment of venous thromboses in various vascular areas, including deep and superficial leg vein thromboses, vena cava thromboses, thromboses of the renal and hepatic veins including veno-occlusive disease, for the prevention and treatment of pulmonary embolism, for the treatment of patients with all forms of coronary heart disease, including the acute form, as unstable angina pectoris or acute myocardial infarct, and the chronic form, as stable angina pectoris, or in patients with post-myocardial infarct condition, for preventing acute and chronic reocclusions after bypass operations on all vascular areas and after angioplasty (PT(C)A), and for preventing occlusion in patients with peripheral arterial diseases, for treating stroke in its acute form, in the chronic form in patients with post-stroke conditions and for primary prophylaxis in patients with stenoses of the afferent cerebral arteries.
The benzimidazoles mentioned above may also be used to treat patients on kidney replacement therapy. This comprises both anticoagulation during the use of kidney replacement therapy to keep the system open and also treatment of the system activation of clotting such as occurs in patients on kidney replacement therapy, both in patients undergoing chronic haemodialysis and in those undergoing a process of veno-venous or arterio-venous chronic filtration. Accordingly, both patients with chronic kidney failure and patients with acute kidney failure may be treated irrespective of the cause of the kidney failure. This also includes the prevention and treatment of blockage of the dialysis shunt.
The abovementioned pharmacologically valuable properties of the benzimidazole derivatives disclosed in the prior art constitute the basic prerequisite for effective use of the compounds as pharmaceutical compositions. However, to be permitted for use as a medicament, an active substance must also satisfy further requirements. These parameters are largely to do with the physicochemical nature of the active substance.
Without being restrictive, examples of these parameters are the stability of effect of the starting substance under various environmental conditions, the stability during production of the pharmaceutical formulation and stability in the final compositions of the drug. The pharmaceutically active substance used to prepare the pharmaceutical compositions should therefore have great stability which is ensured even under all kinds of environmental conditions. This is absolutely essential to prevent pharmaceutical compositions being used which contain breakdown products, for example, in addition to the active substance itself. In such a case the content of active substance present in the pharmaceutical formulation might be lower than specified.
The absorption of moisture reduces the content of pharmaceutically active substance as a result of the increased weight caused by the uptake of water. Pharmaceutical compositions with a tendency to absorb moisture have to be protected from moisture during storage, e.g. by the addition of suitable drying agents or by storing the drug in an environment where it is protected from moisture. In addition, the uptake of moisture may reduce the content of pharmaceutically active substance during manufacture if the pharmaceutical substance is exposed to the environment without being protected from moisture in any way. Preferably, therefore, a pharmaceutically active substance should be only slightly hygroscopic.
As the crystal modification of an active substance is important to the reproducible active substance content of a preparation, there is a need to clarify as far as possible any existing polymorphism of an active substance present in crystalline form. If there are different polymorphism modifications of an active substance care must be taken to ensure that the crystalline modification of the substance does not change in the pharmaceutical preparation later produced from it. Otherwise, this could have a harmful effect on the reproducible potency of the drug. Against this background, active substances characterised by only slight polymorphism are preferred.
Another criterion which may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of manufacturing process is the solubility of the active substance. If for example pharmaceutical solutions are prepared (e.g. for infusions) it is essential that the active substance should be sufficiently soluble in physiologically acceptable solvents. It is also very important for drugs which are to be taken orally that the active substance should be sufficiently soluble.
The problem of the present invention is to provide a pharmaceutically active substance which not only is characterised by high pharmacological potency but also satisfies the above-mentioned physicochemical requirements as far as possible.